Fluid overload states are associated with a number of serious medical conditions. Many cardiac diseases can lead to compromise in the heart's ability to pump blood. Myocardial infarction frequently causes the replacement of heart muscle by fibrotic tissue. This fibrotic tissue is not capable of pumping blood and results in a decrease in the cardiac output. Cardiomyopathy causes the heart muscle to have less strength resulting in reduced cardiac output. These and other cardiac diseases result in blood pooling in the pulmonary vasculature and even in peripheral tissues such as the feet and legs. This congestive heart failure can cause fluid to leak from the vascular space into the extravascular space to cause edema of the tissue involved, e.g. pulmonary edema, edema of the legs, etc. The reduced cardiac output causes lowered blood flow to the kidneys which decreases the urinary output. Diseases of the kidney can also lead to fluid overload states. For example, nephrosis and nephritis cause decreases in the ability of the kidney to excrete urine with resultant fluid retention in the body and formation of edema. Acute and chronic renal failure compromise or eliminate the production of urine, resulting in fluid overload of the body. Intestinal or nutritional disorders can result in decreased serum protein levels. Particularly when the serum albumin levels are decreased, the colloidal pressure in the vascular space is inadequate to retain fluid in the blood vessels and tissue edema forms. These fluid overload states can result from, among other diseases, kwashiorkor, gluten-sensitive enteropathy, and deficiencies of such digestive enzymes as chymotrysin or carboxypeptidase. Hepatic disease can also lead to fluid overload states. Cirrhosis of the liver can result from many liver diseases including any of the hepatitis viruses, alcoholic liver disease, biliary obstructions, hemochromatosis, Wilson's disease, mucopolysaccharidoses, and many other genetic diseases. Cirrhosis of the liver results in decreased synthesis of serum proteins such as albumin. It also causes obstruction to blood flow from the body below the diaphragm to the heart. This obstruction causes increased pressure the vasculature with resultant edema formation below the diaphragm, ascites formation, and decreased blood flow to the kidneys. Disorders of other systems, such as the endocrine (e.g. preeclampsia, eclampsia, etc.), neurological (e.g. angioneurotic edema, etc.), or immune systems can also cause fluid overload states. Hormonal alterations, such as the syndrome of inappropriate antidiuretic syndrome and states with high progesterone levels, can result in fluid retention and overload. Pulmonary diseases, such as pulmonary fibrosis and chronic obstructive pulmonary diseases, also result in fluid overload states. This listing of diseases and syndromes is merely illustrative of some of the conditions which can cause fluid overload states and is not intended to be exhaustive.
In addition to the fluid overload, many of these conditions cause buildup of other substances. Any condition that compromises urinary output can result in increases in urea, creatinine, other nitrogenous waste products, and electrolytes or minerals such as sodium, phosphate, and potassium. Hepatic diseases can result in retention of water along with substances normally processed by the hepatocytes such as ammonia and various organic acids. Cardiac disorders can result in build up of lactic acid or lactates due to ischemia of various tissues.
In addition to conditions that cause fluid overload, there are many medical conditions where fluid is not being appropriately distributed throughout the body, whether or not there is actual excess of total body fluid, referred to herein as “fluid mal-distribution states”. These conditions include such conditions as altitude sickness, diabetes, physiological changes of aging, some types of nocturia, some types of pre-menstrual syndrome, capillary protein leak syndrome, pregnancy, some forms of hypertension, post operative fluid retention, obesity, chronic renal insufficiency, side effects from chemotherapy, and others. Nocturia, the need for passage of urine more than twice during the night, has many causes. Some patients have an overactive bladder which awakens them several times per night. Other patients have an osmotic diuresis during the night, such as glucosuria in diabetic patients. Many patients have a fluid diuresis during the night secondary to saline retention during the day. Such saline retention typically occurs with fluid accumulation in the dependent extremities. During the night, the extremities are repositioned to be at the same level as the heart, and the saline diuresis begins. These patients frequently pass 500 to 1500 mL of urine per night. Since the normal bladder capacity is about 250 mL, these patients may have nocturnal micturition as many as five times per night. Hypertension is another symptom which may result from fluid overload or fluid mal-distribution. Such patients can frequently be identified by their response to a diuretic. A patient with fluid-responsive hypertension will usually show a decrease in systolic and/or diastolic blood pressure after a dose of rapid acting diuretic or a dialysis procedure. However, such patients resist chronic administration of diuretics since these medications interfere severely with quality of life and sleep. Even hypertension that is not responsive to acute fluid removal, such as vaso-constrictive hypertension, may respond to chronic administration of diuretics.
If untreated, the build up of water (i.e. fluid overload) and other blood borne waste products can lead to unpleasant symptoms and serious medical complications. Peripheral edema can be painful and cause clothing to be too tight. The swelling from the edema can compromise the blood flow to or from the tissues resulting in infections or ulcers. Pulmonary edema causes difficulty in absorbing enough oxygen to properly oxygenate tissues. Ascites can be quite painful. Edema of the intestine secondary to liver disease causes malabsorption of nutrients leading to malnutrition. Disease of the kidney can cause build up of uremic toxins such as putrescine, xanthine, and creatinine. Ammonia retention can result in neurological damage. Any organic acid in excess can cause metabolic acidosis with resultant dysfunction of pH dependent processes such as enzymatic metabolic reactions. Ischemic tissues with increased lactic acid can be compromised in function or even necrose.
Treatment for fluid overload states involves both removal of the excess fluid and remediation of the other waste products that are accumulating in the body. Removal of the waste products may be quite different from the treatment for removal of water and may have a different degree of success. A common method of treatment for removal of excess water is fluid restriction. When fluid intake is less than the fluid output through urinary losses, fecal losses, and insensible losses (e.g. sweat, moisture in the breath, etc.), fluid is removed from the body and the fluid overload state can be treated. This method of treatment is not usually adequate for fluid removal and is not designed to remove other metabolic wastes. As such, it is not usually the sole treatment of a fluid overload state.
Another common treatment for fluid overload states is administration of diuretic agents. Diuretic agents alter the normal kidney function to either increase the amount of plasma filtrate produced or decrease the reabsorption of tubular fluid. These agents usually interfere with the normal renal handling of electrolytes. For instance, furosemide interferes with normal sodium reabsorption from the tubules and results in excessive wasting of sodium and potassium. Increasing the dietary sodium usually worsens the fluid overload state, but not increasing the dietary sodium frequently results in decreased total body sodium and decreased serum sodium concentrations. This eventually makes the patient resistant to the diuretic. Diuretic resistance may also result from the fluid overload being confined to the extravascular space while the diuretic can only alter the retention of fluid in the intravascular space.
Dialysis is a common treatment for those suffering from fluid overload states and toxic accumulations of metabolic wastes. Both compromised renal function and compromised hepatic function have been treated with dialysis. Dialysis most commonly takes one of two forms, hemodialysis or peritoneal dialysis. Both forms of dialysis remove excess water and waste products (e.g. urea, salts, etc.) from the body. However, hemodialysis and peritoneal dialysis involve significant patient discomfort and/or inconvenience. In addition, removal of water and wastes through dialysis is not uniform for all substances. Sodium and potassium are easily removed during either peritoneal dialysis or hemodialysis. Urea is relatively easily removed. Creatinine and phosphate have lower removal rates, and proteins such as beta-2-microglobulin have markedly lower clearances. Removal rates for hepatic toxins are quite low unless modifications are made to the typical hemodialysis equipment and solutions. One method being used is to add albumin to the dialysate to facilitate removal of toxins which are carried on albumin in the bloodstream.
WO 98/17707 to Simon et. al. published Apr. 30, 1998 describes the therapeutic ingestion of functionalized, water soluble, polyether glycol polymers for the selective absorption of certain blood borne waste (i.e. phosphate and/or oxalate) from in the gastrointestinal (GI) tract. However, the object of this invention is to prevent the absorption of dietary phosphate and oxalate and does not address fluid overload. This reference is incorporated herein by reference.
Ingestion of oxystarch and coal for treatment of end stage renal dialysis patients has been investigated by Friedman et. al., see Clinical Aspects of Uremia and Dialysis, pg. 671-687 (1977) and see Friedman, et. al., “Combined oyxstarch-charcoal trial in uremia: sorbent-induced reduction in serum cholesterol” Kidney International 1976; 7: S273-6. The aldehydes on the oxystarch are intended to remove urea and the charcoal is intended to remove other organic substrates. However, the fluid capacity of these polymers is limited and not clinically practical as a fluid overload agent.
U.S. Pat. Nos. 5,679,717; 5,693,675; 5,618,530; 5,702,696; 5,607,669; 5,487,888 and 4,605,701 describe the ingestion of a crosslinked alkylated amine polymers to remove bile salts and/or iron from a patient. Again these polymers are limited in their ability to absorb fluids and are not practical for treatment of fluid overload.
U.S. Pat. No. 4,470,975 describes the elimination of water from the gastrointestinal (GI) tract by ingesting an insoluble, hydrophilic crosslinked polysaccharide which absorbs water from the gastrointestinal (GI) tract and is subsequently excreted. This patent is incorporated herein by reference. Unfortunately, the described polysaccharides can be difficult to synthesize and relatively expensive. Moreover, their ability to absorb water or saline on a per-weight basis is limited; thus leading to very high doses to the patient in order to obtain an effective treatment.
Imondi, A. R. and Wolgemuth, R. L reported in “Gastrointestinal sorbents for the treatment of uremia. I. Lightly cross-linked carboxyvinyl polymer” in Ann. Nutr. Metab. 1981; 25: 311-319 on studies of several insoluble resins, two polysaccharide preparations, various oxystarch preparations, and a highly swellable polyacrylic acid for oral use in treating uremia. They note that the polyacrylic acid increased the fecal excretion of urea and total nitrogen to the same extent as oxystarch. Ammonia, sodium, potassium, calcium, and magnesium were removed by the polyacrylic acid while phosphate, the only anionic species investigated, was not removed by the polyacrylic acid. Oxystarch and the polyacrylic acid increased fecal fluid excretion to the same degree—which is inadequate for clinical utility, as revealed above in the discussion of Friedman's articles on oxystarch.
Japanese Patent Application Kokai No. H10-59851 (Application No. H8-256387) and Japanese Patent Application Kokai No. H10-130154 (Application No. H8-286446) disclose the oral administration of alkali metal and alkaline earth salts of crosslinked polyacrylates to treat kidney disease. These polymers are administered orally from an oil emulsion. Thus, the water absorption effect of the polymer begins within the stomach, just as is the case in the experiments reported by Imondi and Wolgemuth. Such direct exposure to stomach acid can lead to significant polymer degradation due to the low pH environment. Moreover, the polymer tends to absorb nutrients from the body via the stomach along with becoming saturated with fluid just ingested rather than fluid containing uremic wastes such as urea and creatinine. Thus, although the disclosed polymers absorb significantly more water or saline than polysaccharides on a per weight basis, direct exposure to stomach acid can result in undesired polymer degradation, absorption of nutrients, and polymer saturation with ingested fluid rather than the absorption of excess fluid and waste from the intestinal tract.
U.S. Pat. No. 4,143,130 discloses the oral administration of lightly crosslinked polyacrylic acid for removing calcium from the intestinal tract in order to treat kidney stones. The polymer may be provided as a gel with hydroxyethylcellulose in a tablet, capsule or pill form which may be enterically coated, although no examples are provided. The aim of this invention was to remove calcium from the body—not fluids. In fact the preferred method of administration included adding water to the formulation prior to administering to the patient. Thus, there was no suggestion that this polymer could be used to treat fluid overload states or remove metabolic waste products or fluid from the intestinal tract.
U.S. Pat. No. 5,051,253 discloses the oral administration of polyacrylic acid for treating mucolytic protease activity in patients with inflammatory bowel disease. The polymer may be provided with a EUDRAGIT coating. The aim of this invention was to administer small amounts of a gel to the colon to coat the mucosa and protect it from degradation by protease. Treatment of fluid overload was not suggested. Removal of metabolic wastes was not anticipated or desired.
Polycarbophil is a synthetic oral bulk-producing laxative based upon the calcium salt of polyacrylic acid. Calcium polycarbophil can absorb up to 60 times its weight in water or 6 times its weight in 0.9% saline. Polycarbophil is known for use in the treatment of constipation and diarrhea and is commonly orally administered with 250 milliliters of water per 500 mg dose.
Although these literature references evidence attempts to provide orally administered substances, such as polysaccharides, polystarches, polyaldehydes, activated charcoal, and polyacrylic acid compounds, none evidence a successful approach to removing fluid from the GI tract. Most of the agents have had inadequate fluid absorbing capacity. Agents with larger capacities for fluid absorption, i.e. sodium polyacrylate or potassium polyacrylate, were not disclosed as agents for treatment of fluid overload states or for absorption of fluid from the GI tract. Calcium polyacrylate, which does not absorb as much fluid (see Japanese Patent Application Kokai No. H10-130154, Application No. H8-286446, see Claim 5 and Table 1) was chosen by one group. Polyacrylic acid, which also does not absorb a large amount of fluid, was chosen by the other group and was directed at prevention of renal stones rather than treatment of fluid overload or removal of fluid from the GI tract (see U.S. Pat. No. 4,143,130). No explanations of these choices are given. The current investigators have found that orally administered polyacrylates exposed to acidic conditions common in the stomach do not absorb fluid as well after exposure to acid, begin their absorption of fluid in the stomach where most fluid is recently ingested fluid, and interfere with normal absorption of nutrients and medications.
Therefore, there continues to be a need for an effective means for removing fluid from the GI tract of a host, removing fluid that is poorly distributed in a host, and for treatments for fluid overload states. Such a treatment should ensure fluid removal occurs substantially in the intestinal tract rather than the stomach, thus avoiding polymer degradation, absorption of nutrients and saturation with ingested fluid. Furthermore, treatments are sought which can selectively remove blood borne waste products, e.g. urea, phosphate, salts, etc.